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Transport of the glutathione conjugate of ethacrynic acid by the human multidrug resistance protein MRP

Author: Zaman, G.J.R. · Cnubben, N.H.P. · Bladeren, P.J. van · Evers, R. · Borst, P.
Type:article
Date:1996
Institution: Instituut CIVO-Toxicologie en Voeding TNO
Source:FEBS Letters, 1-2, 391, 126-130
Identifier: 38407
doi: doi:10.1016/0014-5793(96)00718-1
Keywords: Adenosine Monophosphate · ATP-Binding Cassette Transporters · Biological Transport · Carcinoma, Non-Small-Cell Lung · Cell Membrane · Drug Resistance, Multiple · Ethacrynic Acid · Glutathione · Humans · Kinetics · Lung Neoplasms · Multidrug Resistance-Associated Proteins · Recombinant Proteins · Saccharomyces cerevisiae · Sulfinpyrazone · Transfection · Tumor Cells, Cultured

Abstract

The multidrug resistance protein MRP has been shown to mediate the transport of glutathione S-conjugates across membranes. In this study we demonstrate that the glutathione S-conjugate of the diuretic drug ethacrynic acid, which is an efficient inhibitor of glutathione S-transferases, is a high-affinity substrate and inhibitor of the glutathione S-conjugate pump associated with MRP. This implies that ethacrynic acid may modulate drug resistance of tumor cells not only by inhibiting glutathione S-transferase activity, but also by inhibiting the export of drug conjugates from the cell by MRP. Chemicals/CAS: Adenosine Monophosphate, 61-19-8; ATP-Binding Cassette Transporters; Ethacrynic Acid, 58-54-8; Glutathione, 70-18-8; Multidrug Resistance-Associated Proteins; Recombinant Proteins; Sulfinpyrazone, 57-96-5